The invention relates to tumor-inhibiting platinum (II) oxalate complexes and their use as therapeutic agents, in particular as tumor-inhibiting medicaments.
It is known that some platinum complexes have tumor-inhibiting effects. Apart from cisplatinum, carboplatinum and oxaliplatinum with the following structure
represent the two most important known platinum active substances for combating tumors, wherein in oxaliplatinum the leaving group of the complex with its use as an anti-tumor agent is oxalate. In particular, cisplatinum however has serious side-effects, such as renal toxicity, myelosuppression and ototoxicity.
Therefore, especially oxaliplatinum has, with a bidentate trans-R,R-1,2-diaminocyclohexane ligand and a similarly bidentate oxalato ligand with an effective spectrum deviating from the other two platinum (II) complexes, interesting properties as a cancer therapeutic agent. An advantage with the use of oxaliplatinum as an anti-tumor agent is particularly its lower toxicity in comparison to cisplatinum. However, oxaliplatinum has other undesirable side-effects, such as strong neuropathy.
So far, for the modification of this basic framework and the complex properties the leaving group of the complex was varied. Therefore, in U.S. Pat. No. 4,168,846 cis-platinum (II) complexes with trans-L-1,2-diaminocyclohexane as the ligand without substituents on the cyclohexane ring are described, wherein the complexes, apart from oxalate, have as leaving group malonate and substituted derivatives of malonic acid.
The use of higher dicarboxylic acids or dicarboxylic acid derivatives as ligands in platinum (II) complexes, such as malonate or succinate, is, for example, also described in JP 61-037794.
Furthermore, a range of platinum (II) complexes with monodentate anions, such as pyrophosphate, is described in U.S. Pat. No. 4,234,500.
Also, platinum (II) complexes are known which have a modified diaminocyclohexane ligand. For example, in U.S. Pat. No. 4,359,425 platinum (II) complexes are described, which have a special diaminocyclohexane ligand, which is bicyclical and is bridged on the two carbon atoms adjacent to the amino groups by a (CH2)n bridge where n=1 or 2. In U.S. Pat. No. 4,670,458 dihydroxylised diaminocyclohexane derivatives are disclosed as diaminocyclohexane ligands.
In addition, substituted cyclohexane derivatives, which have pyrophosphate as the leaving group, are described in U.S. Pat. No. 4,291,027.